The present invention relates to novel flavanone derivatives; a process for preparing same; a pharmaceutical composition containing same for treating or preventing an elevated blood lipid level-related disease, inhibiting the activity of acyl-CoA:cholesterol-O-acyltransferase(ACAT) and inhibiting the activity of 3-hydroxy-3-methylglutaryl CoA(HMG-CoA) reductase.
In recent years, coronary artery diseases, e.g., atherosclerosis and hypercholesterolemia, have increasingly become a major cause of deaths. It has been reported that an elevated plasma cholesterol level causes the deposition of fat, macrophages and foam cells on the wall of blood vessels, such deposit leading to plaque formation and then to atherosclerosis(Ross, R., Nature, 362, 801-809(1993)). One of the methods for decreasing the plasma cholesterol level is alimentotherapy to reduce the ingestion of cholesterol and lipids. Another method is to inhibit the absorption of cholesterol by inhibiting enzymes involved therein.
Acyl-CoA:cholesterol-O-acyltransferase(ACAT) promotes the esterification of cholesterol in blood. Foam cells are formed by the action of ACAT and contain a large amount of cholesterol ester carried by low density lipoproteins. The formation of foam cells on the wall of artery increases with the ACAT activity, and, accordingly, an inhibitor of ACAT may also be an agent for preventing atherosclerosis. Further, it has been reported that the blood level of LDL-cholesterol can be reduced by inhibiting the ACAT activity(Witiak, D. T. and D. R. Feller(eds.), Anti-Lipidemic Drugs: Medicinal, Chemical and Biochemical Aspects, Elsevier, pp159-195(1991)).
Therefore, numerous efforts have been made to develop medicines which inhibit ACAT activity; and, as a result, several compounds isolated from the cultures of various microorganisms have been reported. Examples of such compounds include pyripyropenes isolated from the culture of Aspergillus fumigatus(S. Omura et al., J. Antibiotics, 46, 1168-1169(1993)) and Acaterin isolated from Pseudomonas sp.(S. Nagamura et al., J. Antibiotics, 45, 1216-1221(1992)).
Further, it has been reported that hypercholesterolemia can be treated effectively by reducing the rate of cholesterol biosynthesis through the inhibition of HMG-CoA reductase which mediates the synthesis of mevalonic acid, an intermediate in a biosynthesis of sterol or isoprenoids(Cardiovascular Pharmacology, William W. Parmley and Kanu Chatterjee Ed, Wolf Publishing, pp8.6-8.7, 1994).
Accordingly, numerous efforts have been made to develop medicines to inhibit HMG-CoA reductase; and, as a result, several compounds derived from Penicillium sp. and Aspergillus sp. have been commercialized. Specifically, Lovastatin(copyright) and Simvastatin(copyright) developed Merck Co., U.S.A., and Pravastatin(copyright) developed by Sankyo Co., Japan, have been commercialized(C. D. R. Dunn, Stroke: Trends, Treatment and Markets, SCRIPT Report, PJB Publications Ltd., 1995). However, these medicines are very expensive and a long-term administration thereof is known to induce an adverse side effect of increasing creatine kinase in the liver. Accordingly, there has continued to exist a need to develop an inexpensive and non-toxic inhibitor of HMG-CoA reductase.
On the other hand, deterioration of hepatic functions may occur due to an excessive intake of alcohol or foods having a high lipid content, or an infection of hepatitis B or C virus, and it may develop into hepatitis, hepatocirrhosis or hepatic cancer. In particular, the excessive intake of fat-containing foods and alcohol causes fatty liver wherein a large amount of lipids is deposited in the liver tissue and the levels of serum GOT(glutamate-oxaloacetate transaminase), GPT(glutamate-pyruvate transaminase) and xcex3-GTP(xcex3-glutamyl transpeptidase) are elevated(T. Banciu et al., Med. Interne., 20, 69-71(1982); and A. Par et al., Acta. Med. Acad. Sci. Hung., 33, 309-319(1976)). Accordingly, there has continued to exist a need to develop non-toxic agents for preventing and treating elevated blood lipid level-related diseases, and hepatic diseases.
The present inventors have reported that naringenin and hesperetin, which are the aglycons of naringin and hesperidin found in lemons, grapefruits, tangerines and oranges(Citrus sinensis), have activities for inhibiting hyperlipidemia and atherosclerosis (U.S. Pat. Nos. 5,877,208 and 5,763,414).
The present inventors have continued to screen compounds having the flavanone core structure; and have discovered that certain novel flavanone derivatives have enhanced activity in treating or preventing elevated blood lipid level-related diseases, inhibiting an activity of acyl-CoA:cholesterol-O-acyltransferase(ACAT) and inhibiting an activity of 3-hydroxy-3-methylglutaryl CoA(HMG-CoA) reductase.
Accordingly, it is an object of the present invention to provide novel flavanone derivatives.
It is another object of the present invention to provide a process for the preparation of the inventive flavanone derivatives.
It is a further object of the present invention to provide a pharmaceutical composition for treating or preventing an elevated blood lipid level-related disease, inhibiting an activity of acyl-CoA:cholesterol-O-acyltransferase(ACAT) and inhibiting an activity of 3-hydroxy-3-methylglutaryl CoA(HMG-CoA) reductase.
It is a further object of the present invention to provide a method for treating or preventing an elevated blood lipid level-related disease, inhibiting an activity of acyl-CoA:cholesterol-O-acyltransferase(ACAT) and inhibiting an activity of 3-hydroxy-3-methylglutaryl CoA(HMG-CoA) In accordance with the present invention, there is provided a novel compound of formula (I): 
wherein,
R1 is R5 or R6CO group;
R2 is H or R6CO group;
R3 is H, CH3, R5 or R6CO group;
R4 is H, OH, OR5 or R6COO group;
R5 is a C2-5 alkyl group substituted with a phenyl group optionally having one or more substituents selected from the group consisting of C1-3 alkyl, OH, Cl and NO2; a C1-5 alkyl group substituted with a naphthyl group optionally having one or more substituents selected from the group consisting of C1-3 alkyl, OH, Cl and NO2; a C10-18 alkyl; or a C10-18 alkenyl group; and
R6 is a C10-18 alkenyl group; or an aryl group optionally having one or more substituents selected from the group consisting of C1-3 alkyl, OH, Cl or NO2.